JPS6058913B2 - Method for producing 2-mercaptopyrimidine hydrochloride - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 2-mercaptopyrimidine hydrochloride.

2-Mercaptopyrimidine hydrochloride is useful, for example, as a precursor of 2-butyloxycarbonylthiopyrimidine derivatives, which are amino acid protecting agents during peptide synthesis.

As a method for producing 2-mercaptopyrimidine hydrochloride, a method is known in which a β-dicarbonyl compound such as thiourea or acetylacetone is reacted with hydrogen chloride, as shown in the reaction formula below.

(Refer to Special Publication No. 51-5390) H2NCH3Cσ,
HCI NC■S + N°C H2 H2N·' CH3C0−/ niSOSH−HCl+2H20 ←• Conventionally, this reaction has been carried out using an ethanol solvent with low solubility in order to improve the yield of the product.

When carrying out this reaction industrially, it is economically advantageous to reuse the solvent used in the reaction in the reaction after separation of the products, regardless of whether the reaction is repeated batchwise or continuously. After the reaction, the solvent will contain water produced by the reaction, so if this solution is used as is for the next reaction, the solubility of the raw materials and products will change, so the reaction conditions must be set constant. I can't. This tendency gradually increases with the number of times the solvent is reused. On the other hand, the above reaction is carried out by supplying hydrogen chloride as an aqueous hydrochloric acid solution to the reaction, but the solvent after the reaction also contains water in the aqueous hydrochloric acid solution, increasing the amount of solvent after the reaction. Therefore, if the entire amount is reused as is, the reaction conditions may change.

In view of the above circumstances, the present inventors have proposed various methods for industrially advantageous production of 2-mercaptopyrimidine hydrochloride by reacting thiourea and a β-dicarbonyl compound in the presence of hydrochloric acid through repeated batch reactions or continuous reactions. As a result of our studies, we found that when a certain reaction method is adopted, even if the solvent after the reaction is reused, the reaction conditions do not change much, and the product can be obtained in high yield. completed.

That is, the gist of the present invention is that the general formula (R1 and R2 represent a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, R1
and R2 may be the same or different)
-Dicarbonyl compound is reacted with thiourea and hydrogen chloride to form a compound of the general formula (R1 and R2 are the same as the above general formula (1))
In the method for producing 2-mercaptopyrimidine hydrochloride represented by The present invention relates to a method for producing 2-mercaptopyrimidine hydrochloride, characterized in that the bottom liquid after separation is reused as a reaction solvent.

To explain the present invention in detail, examples of the β-dicarbonyl compound represented by the general formula (1) used in the present invention include acetylacetone, 2-carbonyl-butyraldehyde, and the like.

The amount of the β-dicarbonyl compound used is usually 0.8 to 1 times the molar amount of thiourea. If the amount of the β-dicarbonyl compound used is too small, unreacted thiourea will be contained in the product, and if it is too large, it will be uneconomical and undesirable. In the present invention, it is essential to use water alone as a solvent, which increases the reaction rate compared to conventional ethanol solutions, and furthermore,
This is preferable because it produces less by-products.

The ratio of the raw materials to be used and the water solvent is preferably, for example, 0.2 to 4.0 moles of thiourea to 1k9 of water. If the proportion of thiourea is too small, the crystallization operation after the reaction will be difficult, while if it is too large, a large amount of product will precipitate during the reaction, making it difficult to carry out the reaction well, which is not preferable. In the present invention, hydrogen chloride is supplied in gaseous form. As a supply method, gas may be supplied directly to the reactor, but after filtration, hydrogen chloride gas is introduced into the furnace liquid to be reused for the reaction. It is preferable to carry out the reaction after absorbing .

In this case, the amount of hydrogen chloride absorbed is equal to or more than the equivalent mole of thiourea, and is preferably adjusted to an excess amount of 0.2 to 5 moles per kg of water. Since hydrogen chloride is used in the present invention, the amount of solvent after the reaction does not increase significantly, making it suitable for reusing the solvent. The reaction between thiourea and the β-dicarbonyl compound is usually carried out at a temperature of 65° C. or higher, preferably 70 to 95° C., and the residence time is one or more times.

After the reaction, the reaction mixture is cooled and crystallized to precipitate the generated 2-mercaptopyrimidine derivative crystals, and then the product is separated and recovered by, for example, filtration or centrifugation. Although the conditions for cooling crystallization vary somewhat depending on the reaction conditions, it is usually preferable to separate the precipitate by cooling to 30° C. or lower. In the present invention, the liquor liquor from which the product has been separated is reused as a solvent for the above-mentioned reaction.

In the reaction of the present invention, only a small amount of water is produced,
Subtracting the solvent loss during crystal separation, there is almost no increase in the amount of solvent, so it can be reused as is for the next reaction. Also.
You may purge some of the liquid and add a corresponding amount of water before use. According to the present invention, since an inexpensive aqueous solution is used and hydrogen chloride is supplied as a gas, even if the p liquid after the reaction is reused as it is for the next reaction, the reaction content will not change, so the same reaction conditions can be used. There is no problem in carrying out the reaction.

Therefore, it was ultimately excluded. The amount of wastewater discharged may be small, so wastewater treatment is simple. Furthermore, since the solubility of the product is high due to the use of an aqueous solvent, it is possible to carry out a uniform reaction even if a larger amount of raw material is supplied than in the case of an ethanol solvent, and moreover, by-products are not produced. It also has the effect of being small.

Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to the following Examples unless the gist thereof is exceeded.

Example 7 of water in a reactor with a stirrer, a reduction condenser and a heating device
76.1q (1 mol) of 30q1 thiourea and 110y (1.1 mol) of acetylacetone were added, and the mixture was heated to 40°C for dissolution treatment.

Next, 273y (2 moles) of hydrogen chloride gas was blown into the solution in one powder and absorbed, and then the temperature was raised to 80° C. over 30 minutes, and the reaction was carried out at 80° C. for 2.5 hours. After reaction, 20'
After cooling to 4C and holding for 3C to perform crystallization,
Filtering crystals of 6-dimethyl-2-mercaptopyrimidine hydrochloride? more separated. The total amount of liquor obtained by separating the crystals was used as a solvent, and the amount of hydrogen chloride gas was reduced to 36.5y (1
The reaction was repeated in exactly the same manner as above except that the amount of mol) was changed.

Repeat this reaction three times, and each reaction! The product yield, thiourea content, and by-product content in the reaction were measured.
The results shown in the table were obtained. Comparative Example In the example, the same amount of ethanol containing 1% water by weight was used as the solvent, and the same procedure as in the example was carried out. The reaction was carried out and the results shown in Table 1 were obtained.

From the results in Table 1, it can be seen that the conversion rate of thiofluoride and the yield of hydrochloride are higher in the present invention than in the comparative example, and furthermore, the amount of impurities in the obtained product is also lower.

Claims (1)

[Claims] 1. General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ ---- (1) (R
^1 and R^2 represent a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, and R^1 and R^2 may be the same or different. By reacting with urea and hydrogen chloride, the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
In the method for producing 2-mercaptopyrimidine hydrochloride represented by the formula (R^1 and R^2 have the same meanings as in general formula (1)), water is used as a solvent and hydrogen chloride is supplied in gaseous form. 1. A method for producing 2-mercaptopyrimidine hydrochloride, which comprises carrying out a reaction, crystallizing a mixture after the reaction, separating a precipitated solid, and then reusing the filtration as a reaction solvent. 2. The method for producing 2-mercaptopyrimidine hydrochloride according to claim 1, wherein the β-dicarbonyl compound represented by the general formula (1) is acetylacetone.